17{62 -hydroxy-17{60 -(2{40 -methallyl)9{62 , 10{60 -androsta-1,4,6-trien-3-one, methods of producing this compound and pharmaceutical compositions comprising said compound as an active ingredient

ABSTRACT

A progestationally active 17 Alpha -(2&#39;&#39;-methallyl)-9 Beta , 10 Alpha androsta-1,4,6-triene-3-one. 17 Beta -hydroxy-17 Alpha (2&#39;&#39;-methallyl)9 Beta , 10 Alpha -androsta-1,4,6-trien-3-one, methods of producing this compound and pharmaceutical compositions comprising said compound as an active ingredient.

Unite States Patent 1 1 Westerhoi et al.

[75] Inventors: Pieter Westerhof; Lucas Morsink, both of Van Houtenlaan,Weesp, Netherlands [73] Assignee: U.S. Philips York,N.Y.

[22] Filed: July 13, 1970 [21] App1.No.: 54,616

Corporation, New

Y [30] Foreign Application Priority Data July 16, 1969 Great Britain;..35,86l/69 I45] Mar. 27, 1973 [52] US. Cl. ..260/397.4, 195/51, 424/243[51] Int. Cl ..C07c 169/22 [58] Field of Search Machine SearchedSteroids [56] References Cited UNITED STATES PATENTS 3,362,968 1/1968Reerink et al. ..260/397.4

Primary ExaminerHenry A. French Attorney-Frank R. Trifari [57] ABSTRACTA progestationally active l7a-(2'-methallyl)-9B,10aandrosta-1,4,6-triene-3-one. 17/3-hydroxy-17a-(2'- methallyl )9 B, lOa-androsta-l ,4,6-trien-3-one, methods of producing this compound andpharmaceutical compositions comprising said compound as an activeingredient.

1 Claim, No Drawings l7B-HYIDROXY-l7a-(2'-METIIALLYL)9B, 10a- ANDROSTA-l,4,6-TRIEN-3-0NE, METHODS OF PRODUCING TIIIS COMPOUND AND PHARMACEUTICALCOMPOSITIONS COMPRISING SAID COMPOUND AS AN ACTIVE INGREDIENT It wasfound that the compound 17B-hydroxy-17a- (2 '-metha1lyl)-9B, lOa-androsta-l ,4,6-trien-3-one, which can be represented by the formulaCHa 1 ent-own,

ing to the invention, though very closely related chemically to theabove indicated known compounds, exhibits a progestational activitywhich is about 2-7 times higher than that of the known compounds.

Also the anti-estrogenic activity of the inventive compound proves to beconsiderably higher than that 4 of the known steroids.

When the oral and parenteral progestational activity of the inventivecompound are compared with those of Dydrogesterone, a well-knownprogestational agent with the trade name Duphaston, it appeared that thepresent compound is about 20-30 times'more active than Duphaston.

Due to its high hormonal activity the inventive compound, when worked upto the usual compositions such as tablet, pill, capsule, injectionliquid, may advantageously find use in the treatment of e.g. stopbleeding, climacterial disorders, premature labor, primary and secondaryamenorrhoe and as acontraceptive agent.

The employed dose may vary somewhat according to the nature andseriousness of the condition to be treated. Generally the dose may berelated to that of Duphaston whereby the dose is as much less as theactivity of the present compound surpasses that of Duphaston.

The compound according to the invention is a new chemical substancewhich may be prepared accordingto methods known per se for theproduction of analogous compounds.

Thus the compound according to the invention may be produced accordingto methods which are characterized in that:

a. the compound l7B-hydroxy-l7a-(2'-methallyl)-9B,l0a-androsta-4,6-dien-3-one is subjected to a 1,2-dehydrogenationreaction to introduce a double bond between the carbon atoms 1 and 2;

b. the compound 9B,l0a-a'ndrosta-1,4,6-triene-3,17- dione is reactedwith a Z-methallyl Grignard compound or with an alkali metal 2-methallylcompound, followed by the decomposition of the intermediately formedaddition product.

The above indicated methods (a) and (b) may be explained in more detailas follows. ad a The introduction of a 1,2-double bond can be carriedout according to one of the following processes.

I. By microbiological l-dehydrogenation e.g. with CorynebacteriumSimplex,

A. Nobile, et al., J. Am. Chem. Soc. 77, 4,184 (1955 11. By directl-dehydrogenation l. with iodine pentoxids or periodic acid Dutch Patentapplication 215,154 and 211,626

2. with selenium dioxide,

J.l-I. Fried et al., J. Am. Chem. Soc. 81, 1235 A. Bowers, et al., J.Am. Chem. Soc, 81, 5991 3. with chloranil e.g. for the conversion of3-keto-A4 into 3-keto-1,4,6-steroids,

E.J. Agnello and GD. Laubach, J.Am. Chem. Soc.

4. with 2,3-dichloro-5,6-dicyanobenzoquinone, D.

Burn et al., Proc. Chem. Soc. 1960,14,

5. dehydrogenation of 3-keto-steroids with lead tetra acetate,

R.L. Clarke, J.Am. Chem. Soc. 77, 661 (1955),

R. Joly, Bull, Soc., 366 (1958). 111. by selective1,2-dehydrohalogenation of 2-halo-3- keto-steroids e.g. with an organicbase such as collidine or with lithiumbromide and lithium carbonate indimethyl-formamide,

C. DjerassLJ. Am. Chem. Soc. 71, 1,003 (1949). ad b The processaccording to method (b) deals with the alkenylation of a 17-keto groupby reaction with 1. a Grignard reagent of the formula R-Mg-X, wherein Rrepresents a 2-methallyl group and X stands for a halogen atom.

2. a compound of the formula MeR, wherein Me stands for an alkalimetalatom such as Na, K or Li and R represents a 2-methallyl group.

The reaction with the Grignard reagent proceeds in the presence of asolvent such as ethers for example, diethylether, dioxan ortetrahydrofuran. The reaction with the alkali metal Z-methallyl compoundmay be carried out in liquid Nl-l as the reaction medium, if desired inthe presence of a solvent such as dioxan, tetrahydrofuran ordiethylether. Instead of liquid Nl-l a secondary or teriary aliphaticalcohol, such as propanol-2, tertiary butanol or tertiary amylalcohol,may be used as a reaction medium.

After the alkenylating reaction, the intermediately formed additionproduct may be decomposed in an aqueous medium. such as an aqueousNI-LCl-solution.

ln-some cases it is preferred to protect the 3-keto group during thealkenylating reaction. This can be done for example by converting saidgroup to a derivative which does not react with the reaction medium.

Thus the 3-keto group may be converted eg to a 3- enamine or 3-ketalgroup, followed, after the alkenylating reaction took place, byhydrolysis to reainstall the original 3-keto group.

A 3-enamine group may be prepared by reacting a 3- keto group with asecondary amine such as pyrrolidine. 3-ketals may be produced byreacting a 3-keto group with an aliphatic diol, such as ethylene glycolor propylene glycol.

The compound according to the invention may be worked up topharmaceutical compositions in the usual manner. Thus the compoundaccording to the invention may be compounded in the form of pills,capsules, tablets and in liquid form for oral administration and also beworked up to injection liquids for parenteral administration. Tabletsmay be produced for example by mixing the compound with inert carriermaterial such as sacharose, lactose, amylum together with fillers,surface-active agents or lubricants such as talcum, magnesium stearateor a carboxy-methyl cellulose. Injection liquids can be produced bydissolving a methylene chloride solution of the compound in arachid oiland by subsequent evaporation of the methylene chloride, while workingunder sterile conditions.

The invention may be explained in more detail by the following examples.

Example I Preparation of 17B-hydroxy-17a(2-methallyl)-9fl,l0a-androsta-l ,4,6-triene-3-one To a solution of 3,33 gl7/3-hydroxy-17-(2'-methallyl)-9B,10a-androsta-4.6-dien-3-one and 2.78 gdichlorodicyanobenzoquinone in 92.5 ml dry and purified dioxan wereadded 2.06 ml of a dioxan/hydrogen chloride solution containing 45.9 mgHCl/ml. After stirring in a nitrogen atmosphere at room temperature for90 minutes 300 mg calcium carbonate were added and stirring wascontinued for another minutes. The reaction mixture was filtered and thefiltrate was refluxed in an atmosphere of nitrogen for 90 minutes. Thenthe dioxan was removed in vacuo and the residue dissolved in methylenechloride. This solution was washed with water (three times), 2N sodiumhydroxide solution (four times) and water. The organic layer was driedover sodium sulphate.

After filtration the solvent was removed and the residue chromatographedon silicagel (1:20). Combination of the appropriate fractions and tworecrystallizations from ether yielded finally a pure sample ofl7B-hydroxyl 7--(2'-methallyl)-9B, 1 Our-androsta-l ,4,6 -trien-3-one.Melting point 9799C; (305 nm) 12.100; [a] =467 (CHCI Example ll 2 g of17B-hydroxy-l7a-(2-methallyl)-9B,lOa-androsta-l,4,6-trien-3-one weredissolved in chloroform, which solution was mixed homogeneously, with194 g of lactose. The mixture was dried at 40C during 1 hour. Themixture was wettened with a l0%-ic aqueous solution of 2 g of gelatineand subsequently ground through a 20 mesh sieve. The mixture was driedat 40C during 24 hours, whereupon the granules wereground through a 20mesh sieve. The mixture was weighed and then had added to itproportional amounts of talcum venetum and magnesium stearate in amountsof optimal 25 mg and 2 mg respectively. The resulting mixture washomogenized and worked to tablets of 225 mg each.

Example Ill Injection liquids of l7B-hydroxy-l7a-(2'-methallyl)-9B,l0a-androsta-l,4,6-trien-3-one were produced as follows.

5 g of 17B-hydroxy-l7a-(2-methallyl)-9B,lOa-androsta-l,4,6-triene-3-onewere dissolved in mls of a solution of 2 percent w/v benzylalcohol and46 percent w/v benzylbenzoate in ricinic oil at a temperature of 60C.The solution was cooled to room temperature and replinished to 100 mlswith the ricinic oil solution aforesaid. The mixture was homogenized bystirring and filtrated. Ampouls and vials were filled with the filtratedsolution, subsequently sealed and then sterilized by heating for onehour at C.

What is claimed is:

1. l7B-hydroxy-17a-(2'-methallyl)-9B, drosta-l ,4,6-trien-3-one.

IOa-an-

